The primary goal of this project is to develop novel and useful drugs for the control of pain and drug abuse. Recent years have seen a resurgence of opioid abuse, as well as the need for additional analgesics with limited abuse potential. Our objectives are to identify new lead drug candidates for further development and to identify and characterize modulatory systems that influence opioid action. The project contains three major aims. The first aim addresses the role of the anti-opioid sigma1 receptor system in the modulation of opioid analgesia. Sigma1 agonists potently reverse the analgesic activity of a variety of classes of opioid analgesics while sigma1 antagonists potentiate opioid analgesia. The sigma1 receptor has recently been cloned and will serve as a basis for examining this system at the molecular level. The cloned receptor also can serve as a screening system for potential new drugs. The second aim involves the role of ATP-binding cassette (ABC) transporters in opioid pharmacology. The most prominent member of this category, P-glycoprotein (i.e. mdr) has been implicated in the blood-brain barrier, as well as providing a system for transporting endogenous neuropeptides/transmitters from the brain to the peripheral circulation. It also plays a major role in morphine tolerance, with chronic morphine upregulating its expression. In addition to Pgp, MRP1 also has been implicated in opioid action. The last aim involves further studies with a series of opioid analogs synthesized in the laboratory during the previous granting period. By understanding how opioids and their modulatory systems interact, we hope to develop better approaches towards the management of pain and the discovery of new agents.